Combined chronic dietary exposure to four nephrotoxic metals exceeds tolerable intake levels in the adult population of 10 European countries

Figures & data

Table 1. Metals in the assessment group, their endpoint-specific reference value (ESRV) used in the assessment and data used for the derivation of the ESRV.

Metal	Effect	Reference point	Reference type	Species	UF	Conversion to intake dose	ESRV µg/kg bw/d	Reference
Cadmium	Elevated beta-2-microglobulin levels in urine in female volunteers aged > 50 years	4.0 µg/g creatinine	BMDL05	Human	3.9^a	Relation dietary exposure and urinary cadmium levels in non-smoking Swedish women	0.36	EFSA (2009a); Amzal et al. (2009)
Lead	Prevalence of chronic kidney disease defined as a 50% reduction in the glomerular filtration rate to values below 60 mL/min/1.73 m^2 body surface in male and female adults aged > 20 years	15 µg/L blood	BMDL10	Human	3.16^b	Carlisle-Wade model for relation between dietary exposure and lead levels in blood	0.20	Carlisle and Wade (1992); EFSA (2010b)
iAs	Estimated glomerular filtration rate of <60 mL/min/1.73 m^2 body surface in male and female adults > 40 years	1.56 µg/kg per day	BMDL05	Human	3.16^c	Physiologically based pharmacokinetic model	0.49	Lin YJ et al. (2020)
iHg	Elevated biomarkers of proteins in urine in male and female workers (average age 30 years)	35 µg/g creatinine	NOAEL	Human	10^d	Steady-state equation	0.75	SCOEL (2007)

UF: uncertainty factor; ESRV: endpoint-specific toxicological reference value; BMDL: benchmark dose lower limit, NOAEL no observed adverse effect levels, iAs: inorganic arsenic; iHg: inorganic mercury

^a Chemical-specific adjustment factor as applied by EFSA (2009a).

^b Default assessment factor for intraspecies differences in toxicodynamics.

^c Default assessment factors for intraspecies differences in toxicokinetics.

^d Default assessment factors for intraspecies differences in toxicodynamics and toxicokinetics.

Table 2. Description of the food consumption data of ten different European countries included in the cumulative exposure assessment for chemicals relevant for nephrotoxicity.

	Food consumption survey						Data included in study
Country	Method^a	Years^c	Name^d	Population^e (y)	N total^g	Consumption days^h	Population^i (y)	N^j
Austria (AT)	24-h dietary recall	2016	NATIONAL-2016	18–64	2250	2	18–64	2250
Croatia (HR)	24-h and 48-h dietary recall	2011–2012	NIPNOP-HAH- 2011–2012	18–64	2002	3	18–64	2002
Cyprus (CY)	24-h dietary recall	2014–2017	2014–2017–LOT2	10–76	1016	3	18–64	478
Czech Republic (CZ)	24-h dietary recall	2004–2008	SISP04	4–64	2353	2	18–64	1666
Denmark (DK)	Food record	2005–2008	DANSDA 2005–2008	4–75	2700	7	18–64	1739
France (FR)	FPQb and 24-h dietary recall	2014–2015	INCA3	General population^f	4874	3	adults	1980
Italy (IT)	Food record	2005–2006	INRAN SCAI 2005–2006	0–97	3323	3	18–64	2313
Netherlands (NL)	Food record, 24-h dietary recall	2012–2016	FCS2016_Core	1–80	4313	2	18–64	2849
Portugal (PT)	Food record, 24-h dietary recall	2015–2016	IAN-AF-2015–2016	0–84	6429	2	18–64	3434
Slovenia (SI)	24-h dietary recall	2018	SI.MENU-2018	0–75	1981	2	18–64	1047

^a Method of food consumption survey.

^b FPQ – Food propensity questionnaire.

^c Year(s) in which the food consumption survey was conducted.

^d Name of the food consumption survey.

^e The population addressed, the population included males and females.

^f Due to privacy reasons, French food consumption data contained age groups instead of individual ages.

^g The total number of individuals included in the food consumption survey.

^h The number of consumptions days included in the study.

ⁱ The age of the subpopulation group (adults) included in the assessment.

^j The number of individuals included in the assessment.

Table 3. Exposure estimates (µg/kg bw/d) for the metals cadmium, lead, inorganic arsenic and inorganic mercury across ten European countries

	Cadmium		Lead		Inorganic arsenic		Inorganic mercury
Country	Mean	P95	Mean	P95	Mean	P95	Mean	P95
Lower bound^a^,c
AT	0.3 [0.2–0.4]	0.8 [0.4–1.5]	0.5 [0.4–0.5]	0.8 [0.6–1.1]	0.2 [0.2–0.3]	0.5 [0.4–0.7]	0.08 [0.06–0.11]	0.3 [0.2–0.4]
CY	0.2 [0.2–0.3]	0.5 [0.4–0.7]	0.3 [0.3–0.4]	0.6 [0.5–0.7]	0.3 [0.2–0.5]	1.0 [0.5–2.1]	0.08 [0.04–0.13]	0.2 [0.1–0.3]
CZ	0.3 [0.2–0.4]	0.7 [0.5–1.4]	0.3 [0.3–0.4]	0.6 [0.5–0.8]	0.3 [0.2–0.4]	0.5 [0.3–0.9]	0.04 [0.03–0.05]	0.1 [0.1–0.2]
DK	0.3 [0.2–0.4]	0.5 [0.3–1.1]	0.3 [0.3–0.4]	0.6 [0.5–0.7]	0.2 [0.1–0.2]	0.3 [0.2–0.4]	0.04 [0.02–0.06]	0.09 [0.05–0.2]
FR	0.4 [0.3–0.5]	1.1 [0.6–2.4]	0.4 [0.3–0.5]	0.7 [0.6–0.9]	0.2 [0.2–0.3]	0.5 [0.3–0.8]	0.09 [0.08–0.1]	0.3 [0.3–0.4]
HR	0.3 [0.2–0.4]	1.0 [0.6–2.0]	0.3 [0.2–0.3]	0.5 [0.4–0.6]	0.2 [0.2–0.3]	0.4 [0.2–0.6]	0.04 [0.02–0.05]	0.1 [0.1–0.2]
IT	0.3 [0.2–0.4]	0.6 [0.5–1.1]	0.4 [0.3–0.4]	0.6 [0.5–0.8]	0.3 [0.2–0.5]	0.5 [0.3–0.9]	0.05 [0.04–0.06]	0.2 [0.2–0.2]
NL	0.2 [0.2–0.3]	0.5 [0.3–0.7]	0.3 [0.2–0.4]	0.6 [0.4–0.7]	0.2 [0.2–0.3]	0.4 [0.3–0.6]	0.07 [0.06–0.08]	0.3 [0.2–0.3]
PT	0.3 [0.2–0.5]	0.9 [0.6–1.7]	0.3 [0.3–0.4]	0.6 [0.5–0.6]	0.2 [0.1–0.4]	0.6 [0.3–1.1]	0.09 [0.05–0.1]	0.2 [0.2–0.4]
SI	0.3 [0.2–0.6]	0.4 [0.3–1.1]	0.3 [0.2–0.3]	0.5 [0.4–0.6]	0.2 [0.1–0.2]	0.4 [0.2–0.5]	0.04 [0.03–0.05]	0.1 [0.1–0.2]
Upper bound^b^,c
AT	0.6 [0.5–0.8]	1.4 [0.9–2.2]	1 [0.8–1.1]	1.7 [1.5–2.1]	0.4 [0.4–0.5]	0.8 [0.7–1.0]	0.4 [0.3–0.6]	1.1 [0.7–1.5]
CY	0.5 [0.4–0.7]	0.9 [0.6–1.7]	0.8 [0.7–0.9]	1.5 [1.2–1.9]	0.5 [0.4–0.7]	1.3 [0.7–2.3]	0.3 [0.2–0.4]	0.5 [0.4–0.7]
CZ	0.5 [0.4–0.7]	1.1 [0.8–1.6]	0.7 [0.6–0.8]	1.3 [1.1–1.4]	0.5 [0.4–0.7]	0.8 [0.6–1.2]	0.3 [0.2–0.4]	0.7 [0.4–1.0]
DK	0.5 [0.3–0.8]	1.0 [0.6–1.7]	0.9 [0.7–1.0]	1.4 [1.1–1.6]	0.4 [0.3–0.5]	0.6 [0.5–0.7]	0.3 [0.2–0.4]	0.6 [0.4–0.9]
FR	0.7 [0.5–0.9]	1.6 [1.1–2.8]	0.9 [0.8–1.1]	1.6 [1.3–2.4]	0.5 [0.4–0.5]	0.9 [0.7–1.1]	0.3 [0.3–0.4]	0.7 [0.6–0.8]
HR	0.5 [0.4–0.6]	1.3 [0.9–2.2]	0.8 [0.7–0.9]	1.5 [1.2–2.0]	0.4 [0.3–0.5]	0.7 [0.6–0.9]	0.3 [0.2–0.4]	0.5 [0.4–0.7]
IT	0.5 [0.4–0.7]	1.1 [0.8–1.5]	1.0 [0.8–1.3]	1.8 [1.2–3.1]	0.5 [0.4–0.7]	0.8 [0.6–1.2]	0.3 [0.3–0.3]	0.6 [0.5–0.7]
NL	0.5 [0.4–0.7]	1.1 [0.7–1.5]	0.8 [0.7–1.0]	1.4 [1.1–2.0]	0.4 [0.4–0.5]	0.7 [0.6–0.9]	0.3 [0.3–0.4]	0.7 [0.6–0.9]
PT	0.6 [0.4–0.9]	1.5 [0.9–2.2]	0.8 [0.7–0.8]	1.4 [1.2–1.8]	0.5 [0.4–0.6]	0.9 [0.7–1.4]	0.3 [0.3–0.4]	0.6 [0.5–0.7]
SI	0.6 [0.4–0.9]	1.2 [0.7–2.1]	0.6 [0.5–0.8]	1.2 [0.9–1.7]	0.3 [0.3–0.4]	0.5 [0.4–0.8]	0.3 [0.2–0.3]	0.5 [0.4–0.8]

^a In the lower bound scenario metal concentrations below the limits of quantification were assumed to equal zero.

^b In the upper bound scenario metal concentrations below the limits of quantification were assumed to equal the value of the limit of quantification.

^c Values between brackets indicate the 95% uncertainty interval around the exposure estimates.

Figure 1. Distribution of personalised modified reference point indices (pmRPI) for metals relevant to kidney disease (cadmium, lead, inorganic arsenic and inorganic mercury) for adults aged 18–64 years in ten European countries in the lower bound scenario. AT: Austria; CY: Cyprus; CZ: Czech Republic; DK: Denmark; FR: France; HR: Croatia; IT: Italy; NL: Netherlands; PT: Portugal; SI: Slovenia. Dotted lines indicate a pmRPI of 1. Green bars indicate a pmRPI less than one, red bars indicate a pmRPI larger than 1.

Table 4. Classical modified reference point index (mRPI|) and personalised mRPI at mean and high (P95) exposure percentiles for metals relevant to kidney disease (lead, cadmium, inorganic arsenic and inorganic mercury) calculated for the adult population of ten European Countries.

	Classical mRPI				Personalised mRPI
	Mean^d		P95^d		Mean		P95
Country^a	LB^b	UB^c	LB	UB	LB	UB	LB	UB
AT	3.9 [3.0–4.4]	8.0 [6.5–9.5]	7.6 [5.2–11.6]	15.5 [12.4–20.7]	3.7 [3.1–4.3]	8.3 [7.5–9.2]	6.8 [5.5–9.0]	14.5 [12.4–16.9]
CY	2.8 [2.5–4.0]	6.8 [6.0–8.4]	6.7 [4.8–10.3]	13.3 [9.6–19.9]	2.9 [2.6–3.4]	6.7 [6.0–7.5]	5.8 [5.1–7.8]	12.2 [10.5–14.6]
CZ	3.0 [2.5–4.0]	6.3 [5.2–7.9]	6.1 [4.6–9.9]	12.1 [9.5–15.2]	3.2 [2.7–3.6]	6.6 [6.1–7.2]	6.0 [4.8–7.6]	11.4 [10.2–12.9]
DK	2.8 [2.3–3.6]	7.1 [5.2–8.8]	5.1 [3.8–7.6]	11.8 [8.7–15.4]	2.9 [2.5–3.4]	7.1 [6.8–8.0]	4.5 [3.8–6.0]	11.0 [9.5–12.8]
FR	3.6 [2.9–4.6]	7.9 [6.6–9.6]	8.0 [5.7–13.3]	15.2 [11.8–23.1]	3.6 [3.1–4.2]	7.6 [6.8–9.1]	7.4 [5.6–10.8]	13.6 [11.2–18.1]
HR	2.8 [2.0–3.3]	6.6 [5.5–7.7]	6.2 [4.2–10.1]	13.2 [10.3–18.9]	2.7 [2.4–3.2]	6.4 [5.8–7.3]	5.7 [4.4–8.2]	11.7 [9.9–15.0]
IT	3.5 [2.5–4.2]	7.8 [6.3–10.3]	6.0 [4.8–9.2]	14.5 [10.1–23.1]	3.5 [2.9–4.1]	7.9 [6.7–9.8]	6.3 [5.1–7.5]	14.0 [10.8–21.4]
NL	2.6 [2.0−3.6]	6.6 [5.8–8.5]	5.6 [3.7–7.1]	12.4 [9.5–17.2]	2.9 [2.5–3.3]	6.8 [6.1–7.9]	5.0 [4.3–5.7]	11.4 [9.7–14.0]
PT	2.9 [2.3–4.3]	7.1 [5.8–8.3]	7.0 [5.1–10.5]	13.8 [10.6–18.9]	3.2 [2.8–3.6]	7.0 [6.3–8.0]	6.2 [5.3–8.1]	12.6 [10.8–15.0]
SI	2.8 [1.8–3.6]	5.7 [4.6–7.7]	4.6 [3.4–7.3]	11.0 [7.8–17.0]	2.5 [2.0–3.3]	5.8 [4.8–7.1]	4.5 [3.4–5.5]	10.5 [8.2–14.0]

^a AT: Austria; CY: Cyprus; CZ: Czech Republic; DK: Denmark; FR: France; HR: Croatia; IT: Italy; NL: Netherlands; PT: Portugal; SI: Slovenia

^b LB is lower bound scenario. In this scenario analytical values below the limit of detection or limit of quantification were assumed to equal 0.

^c UB is upper bound scenario. In this scenario analytical values below the limit of detection or limit of quantification were assumed to equal the value of the respective limit.

^d Values between brackets indicate the upper and lower boundaries of the uncertainty interval quantified for uncertainties in food consumption and metal concentration data in food due limited sample sizes.

Figure 2. Relative contribution of the individual metals to the personalised mRPI of metals relevant for chronic kidney disease. LB: Lower bound scenario in which values below the limit of quantification equalled 0. UB: Upper bound scenario in which values below the limit of quantification equalled the value of the limit of quantification. Pb: Lead; Cd: Cadmium; iA: inorganic arsenic; iHg: inorganic mercury; AT: Austria; CZ: Czech Republic; CY: Cyprus; DK: Denmark; Fr: France; HR: Croatia; IT: Italy; NL: the Netherlands; PT: Portugal; SI: Slovenia.

Figure 3. Food-metal combination contributing 5% or more to the total combined exposure to metals relevant for chronic kidney disease. LB: Lower bound scenario in which values below the limit of quantification equalled 0. UB: Upper bound scenario in which values below the limit of quantification equalled the value of the limit of quantification. Pb: Lead; Cd: Cadmium; iAs: inorganic arsenic; iHg: inorganic mercury; AT: Austria; CZ: Czech Republic; CY: Cyprus; DK: Denmark; Fr: France; HR: Croatia; IT: Italy; NL: the Netherlands; PT: Portugal; SI: Slovenia.

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